Ethnic Disparities in ST-Segment Elevation Myocardial Infarction Outcomes and Processes of Care in Patients With and Without Standard Modifiable Cardiovascular Risk Factors: A Nationwide Cohort Study

Trials suggest patients with ST-elevation myocardial infarction (STEMI) without ‘standard modifiable cardiovascular risk factors’ (SMuRFs) have poorer outcomes, but the role of ethnicity has not been investigated. We analyzed 118,177 STEMI patients using the Myocardial Ischaemia National Audit Project (MINAP) registry. Clinical characteristics and outcomes were analyzed using hierarchical logistic regression models; patients with ≥1 SMuRF (n = 88,055) were compared with ‘SMuRFless’ patients (n = 30,122), with subgroup analysis comparing outcomes of White and Ethnic minority patients. SMuRFless patients had higher incidence of major adverse cardiovascular events (MACE) (odds ratio, OR: 1.09, 95% CI 1.02–1.16) and in-hospital mortality (OR: 1.09, 95% CI 1.01–1.18) after adjusting for demographics, Killip classification, cardiac arrest, and comorbidities. When additionally adjusting for invasive coronary angiography (ICA) and revascularisation (percutaneous coronary intervention (PCI) or coronary artery bypass grafts surgery (CABG)), results for in-hospital mortality were no longer significant (OR 1.05, 95% CI .97–1.13). There were no significant differences in outcomes according to ethnicity. Ethnic minority patients were more likely to undergo revascularisation with ≥1 SMuRF (88 vs 80%, P < .001) or SMuRFless (87 vs 77%, P < .001. Ethnic minority patients were more likely undergo ICA and revascularisation regardless of SMuRF status.


Introduction
There is growing interest in the outcomes of patients presenting with acute myocardial infarction (AMI) in the absence of 'standard modifiable cardiovascular risk factors' (SMuRFs), (current smoking, hypercholesterolemia, hypertension and/or diabetes mellitus). 1A recent analysis of the SWEDEHEART registry suggests that patients presenting with ST-segment myocardial infarction (STEMI) without SMuRFs, coined 'SMuRFless', have worse 30 day all-cause mortality than those with ≥1 SMuRFs. 1 Mortality in SMuRFless patients' post-STEMI was also found to be higher in the 'Coronary Revascularization Demonstrating Outcome Study' (CREDO-KYOTO) registry, suggested to be due to increased age at presentation and a higher percentage presenting in cardiogenic shock. 2 Conversely, an analysis of non-ST segment myocardial infarction (NSTEMI) patients in the United Kingdom (UK) showed that SMuRFless patients had lower in-hospital mortality than those with ≥1 SMuRFs, although were less likely to receive guideline-directed medical therapy (GDMT), undergo invasive coronary angiography (ICA) and revascularisation. 3With similarities in pathophysiology, risk factors, and clinical outcomes between STEMI and NSTEMI patients, this raises the question as to why the relationship between mortality and the presence of SMuRFs varies according to whether the patients suffer STEMI or NSTEMI. 4ne potential reason is that differences in the population demographics could be contributing to these disparate findings.Ethnic minority patients with STEMI represent a heterogeneous group with presentation at a younger age, increased burden of coronary artery disease (CAD) and higher prevalence of diabetes, hypercholesterolemia and hypertension. 5,6ith the growing evidence suggesting increased mortality in the SMuRFless cohort, our study uses the Myocardial Ischaemia National Audit Project (MINAP) registry to investigate how STEMI outcomes vary depending on the presence of SMuRFs, and whether the outcomes and processes of care vary according to ethnicity within a nationally funded health care system.

Study Design
We used the MINAP, a prospective national registry of patients admitted to hospitals in the UK with acute coronary syndrome (ACS). 7The MINAP dataset consists of 130 variables including baseline demographics and clinical characteristics, comorbid conditions, management strategies, pharmacotherapy, place of care, in-hospital clinical outcomes and diagnoses on discharge. 8,9

Study Population
We included patients admitted with a diagnosis of STEMI in any of the 230 participating hospitals in England and Wales between 1st January 2010 to 31st March 2017, which is the most recent MINAP registry data available at present.The discharge diagnosis of STEMI was determined by local clinicians according to presenting history, clinical examination, and the results of inpatient investigations in keeping with the consensus document of the Joint European Society of Cardiology (ESC) and American College of Cardiology (ACC). 10Patients were excluded if they had missing data in any of the following key variables that defined the 'SMuRFs' group: history of hypercholesterolemia, hypertension, diabetes mellitus, and/ or current smoking.To enable comparison with similar registry-based studies, 1,11 we excluded those with a history percutaneous coronary intervention (PCI), a history of AMI, and a history of coronary artery bypass graft (CABG) surgery.Patients were also excluded if they had missing data regarding in-hospital mortality.Additionally, any individual patient's subsequent admissions were excluded from analysis (Figure 1).This constituted a final cohort of 118,177 patients with STEMI, who were then divided into two subgroups depending on whether they had SMuRFs; group 1: with a history of at least one of the SMuRF variables and group 2 consisting of SMuRFless patients.
A history of SMuRFs was defined as the presence of ≥1 of the following variables from the MINAP dataset (as defined in the MINAP data dictionary); a history of hypertension (a patient already receiving treatment (drug, dietary, or lifestyle) for hypertension or with recorded blood pressure (BP) > 140/ 90 mmHg on at least two occasions prior to admission), a history of hypercholesterolemia (elevation of serum cholesterol requiring dietary or drug treatment), a history of current smoking (a current smoker is a patient regularly smoking an average of ≥1 cigarettes/day, or equivalent, any cigarettes smoked in the last month classify the patient as a current smoker), or a history of diabetes mellitus (any previous diagnosis of diabetes).
We progressed to analyze the baseline characteristics, management strategies, and outcomes of patients with and without SMuRFs stratified by ethnicity.This involved dividing our previously formed ≥1 SMuRFs and SMuRFless groups according to ethnicity.We formed two groups according to ethnicity status in the MINAP dataset: white and ethnic minority.Our Ethnic minority group comprised; Black (including Caribbean, African, Black British, any other Black background), Asian (including Indian, Pakistani, Bangladeshi, Asian British, any other Asian Background but excluding Chinese) and other non-White ethnicity (mixed group including Chinese), according to the classification of ethnicity from the MINAP data dictionary. 12

Outcomes
Primary.Primary outcomes of interest included in-hospital allcause mortality and major adverse cardiovascular events (MACE) (composite endpoint of in-patient all-cause mortality and reinfarction).
Secondary.Secondary outcomes of interest included cardiac mortality (death attributable to myocardial ischemia or infarction, heart failure (HF) and cardiac arrest of unknown cause), and incidence of in-hospital major-bleeding.

Statistical Analysis
Demographics, clinical characteristics, and crude adverse outcomes of patients by vascular bed were compared using the Pearson Chi-squared test for categorical variables.Continuous variables were compared using Student's t-test if normally distributed and using Wilcoxon Rank Sum test if not.Normality of distribution was assessed using Shapiro-Wilks test.Continuous variables are presented as medians and interquartile ranges (IQR) and categorical variables by proportions.Multiple imputations with chained equations (MICE) were used to impute values for variables with missing data, with 10 imputations undertaken MICE is considered to be best practice when dealing with missing data, and can provide unbiased estimates even when levels of missing data are significant, and also some protection when the pattern of 'missingness' is not random. 13For each binary outcome of interest, multivariable logistic regression analysis was applied on imputed datasets to estimate the risk of adverse outcomes between groups.Estimates were combined using Rubin's rules. 14sing our imputed data, adjusted odds ratios (OR) with their 95% confidence intervals (CI) were estimated using a series of hierarchical logistic regression models with patients nested within hospitals using maximum likelihood estimation.Model 1 adjusted for age, sex, year and ethnicity (for the ≥1 SMuRFs vs SMuRFless comparison only), Model 2 adjusted for these, alongside, heart rate, blood pressure, serum creatinine concentration on admission, Killip class and cardiac arrest at presentation.Model 3 adjusted for Model 2 and family history of CAD, left ventricular systolic dysfunction (LVSD), cerebrovascular accident, peripheral artery disease (PAD), asthma/chronic obstructive pulmonary disease (COPD), and Model 4 adjusted for Model 3 plus, ICA, PCI, and CABG surgery during admission.Statistical analysis was carried out using Stata 14.2 (College Station, Texas, USA).A two-tailed P < .05 was considered statistically significant.Tables 1 and 2.

Discussion
Our nationwide analysis of over 100,000 patients hospitalized with STEMI in the UK reveals important findings.First, SMuRFless patients were demographically different compared with patients with ≥1 SMuRFs; being older, more likely to be male and less likely to have common comorbidities such as CeVD and PAD.When stratified by ethnicity, ethnic minority patients were younger and more likely to be male, regardless of the presence of SMuRFs.Second, using a series of hierarchical models, we found that while SMuRFless patients had a slightly higher incidence of in-hospital mortality, cardiac mortality and MACE compared with patients with ≥1 SMuRFs, persisting after adjusting for baseline demographics, Killip class, cardiac arrest and common comorbidities, our study is the first to show that this increased incidence of in-hospital mortality, cardiac mortality and MACE does not persist after adjusting for differences in the provision of ICA, PCI, or CABG surgery during hospital admission.Third, we demonstrate that SMuRFless patients had significant differences in their clinical management; they were less likely to be admitted directly to cardiology wards or under a consultant cardiologist, they were less likely to be treated with GDMT with P2Y12 inhibitors, statins, ACE inhibitors/ARBs and were less likely to undergo ICA or PCI during admission.Fourth, in the first analysis of the role of ethnicity in outcomes of SMuRFless and patients with ≥1 SMuRFs in the UK, we found that ethnic minorities were not disadvantaged in processes of care compared with White patients.Finally, there was no statistically significant relationship between ethnicity and our primary outcomes in SMuRFless patients.
Figtree et al demonstrated the increased 30-day mortality of SMuRFless patients in their analysis of the SWEDEHEART registry. 1Their group had previously demonstrated the increasing proportion of patients with STEMI that were presenting in the absence of SMuRFs, suggesting that the profile of patients suffering STEMI was changing from what we had previously considered as being at particularly high risk, and that these SMuRFless patients also had a higher in-hospital mortality than those with ≥1 SMuRFs. 11,15In an analysis of the CREDO-KYOTO PCI/CABG registry, it was shown that crude all-cause mortality was higher in SMuRFless patients but noted that after adjusting for common confounders such as age, hemodynamic status and medical therapy, there was no statistically significant difference between SMuRF groups with STEMI and NSTEMI but did note increased mortality in their cardiogenic shock subgroup. 2This showed similarity with our results, with our small, demonstrated increases in inhospital mortality, MACE, and cardiac mortality in SMuRFless patients progressively declining after adjusting for more variables with our hierarchical models, losing statistical significance after adjusting for ICA and revascularisation strategy.This suggests that there are a range of factors contributing to the increased observed mortality in SMuRFless patients, but that a potential area for improvement in the outcomes of these patients would be improving the processes of care, particularly with an invasive strategy and the use of GDMT in SMuRFless patients.
The observed increases in mortality in SMuRFless patients following AMI is in marked contrast to the prevailing understanding of cardiovascular risk factors informed by the INTERHEART study, which suggests that a significant proportion of AMI is attributable to nine modifiable risk factors, including all the SMuRF risk factors. 16One consideration is whether the SMuRFless patients are truly SMuRFless, or whether they have just avoided detection prior to admission.The YOUNG-MI registry investigated the prevalence of risk factors in infarction in patients suffering AMI under the age of 50 in multiple US centers, and found that 20% of patients had hypercholesterolemia diagnosed in their index admission with AMI, with diabetes first diagnosed in 22% and hypertension in Figure 3.Primary Outcome between ethnic minority and white patients with SMuRFs.Primary Outcome comparison between ethnic minority and white patients with SMuRFs MACE is defined as composite endpoint of in-hospital death and reinfarction.9% of patients. 17This suggests that a significant proportion of our SMuRFless group may be subsequently diagnosed with one of the standard modifiable cardiovascular risk factors during their index admission, but due to the nature of the MINAP registry data collection, we are unable to adjust for this.
Our results are consistent with those of Figtree et al with regards to discharge pharmacotherapy, highlighting how SMuRFless patients are less likely to be discharged on statins, ACE inhibitors, beta-blockers, and DAPT. 1 They suggested this discrepancy in discharge pharmacotherapy to be a possible mechanism of the increased 30-day mortality in SMuRFless patients, and this could contribute to the in-hospital mortality of patients with longer hospital stays pre-discharge in our study.][20] Our analysis is one of the first to assess whether ethnicity influences the differences in STEMI outcomes according to SMuRF status.In our hierarchical models, we show a small increase in adjusted in-hospital mortality, MACE, and cardiac mortality in White SMuRFLess patients compared with white patients with ≥1 SMuRFs, but this does not persist after adjusting for ICA and revascularisation strategy.The equivalent comparison for ethnic minority patients was showed no statistically significant relationship.In fact, patients from an ethnic minority background were found to have a reduced likelihood of in-hospital death, cardiac mortality, or MACE in our unadjusted data when compared with white patients, were more likely to undergo revascularisation by PCI or CABG and more likely to be treated with P2Y12 inhibitors, beta-blockers, ACE inhibitors/ARBs, and statin therapy.This is consistent with previous work from our group when evaluating the impact of ethnicity on the outcomes of NSTEMI within the UK, where ethnic minority patients were more likely to be prescribed GDMT, undergo ICA and revascularisation. 7We suspect that higher prevalence of comorbidities such as hypertension and diabetes mellitus found in the UK ethnic minority group is leading to a greater perception of risk from CAD, leading to more aggressive treatment in this NSTEMI cohort, but this does not fully explain such high rates of GDMT and revascularisation in our SMuRFless ethnic minority cohort. 21he results from the UK contrast with those from the US, with a recent analysis of the National Inpatient Sample (NIS) where in 159,399 STEMI patients with cardiogenic shock, Black and Hispanic patients had higher in-hospital mortality when compared with White patients, and demonstrated that Black patients were less likely to undergo revascularisation compared with white patients. 5Consistently, studies from the US, show lower rates of GDMT prescription, ICA and revascularisation in ethnic minority groups, which may relate to differences in healthcare funding and equity of access across the two healthcare systems. 22Contemporary studies have now consistently demonstrated an elevated mortality in SMuRFless patients, including large registries from across the world, including the UK, Sweden, Japan, and China, across a range of ethnicities, it is therefore unlikely that the underlying cause for this elevation in mortality is ethnicity-driven. 23It is interesting to note the increased mortality in white SMuRFless patients compared with White patients with SMuRFs in our study, but that this is not the case for the same comparison in ethnic minority patients.A likely reason for this is the greater proportion of females in the White cohort compared with ethnic minority patients in our study, which is in keeping with previous studies of the NSTEMI cohort.7This is in keeping with the work of Figtree et al suggesting that the increased mortality in SMuRFless patients is more pronounced in female patients. 15][26] This is likely to be an important contributor to the increased mortality in the white SMuRFless group compared with those with SMuRFs.Although we excluded patients with takotsubo cardiomyopathy from our analysis, there is always the risk of misclassification in our registry data, which could influence our results.Further studies should be undertaken to identify the reasons for this elevated mortality risk, so that these highrisk patients can be better targeted with early diagnosis of modifiable cardiovascular risk factors, primary prevention and GDMT.
There are important limitations to observational studies like the present one.The MINAP data collection shares the weakness of other national registries, including selfreporting of adverse events with no external validation.Although the MINAP dataset includes important clinical and demographic variables of interest, there are limitations to data collected, such as the lack of frailty score, severity of CAD, socioeconomic factors, access to healthcare, rationale for specific medications or a full list of comorbidities.Our current definition of hypercholesterolemia based upon serum cholesterol levels may not fully capture all patients at risk, with LDL-C levels having been demonstrated to be independently associated with the extent and severity of systemic atherosclerosis, even when at levels that are currently considered at normal. 27The comorbidities in MINAP are typically recorded on admission, meaning that we are unable to include patients diagnosed with a modifiable risk factor during admission, which has meant that our SMuRFless cohort is larger than comparable studies.Patients that were recorded as previous smokers were included to remain consistent with comparable studies, although we acknowledge that these patients may not be truly risk-factor free.The MINAP registry does not record data regarding outcomes following discharge, collecting only in-hospital outcomes, so we are unfortunately unable to replicate the analysis of comparable studies using registries such as SWEDE-HEART. 1 We are unable to differentiate between pre-hospital pharmacotherapy, and medications started as an inpatient from our registry data which is particularly relevant given a potential cause for increased mortality in SMuRFless patients is pre-admission pharmacotherapy. 28,29Due to the demographics of the UK, our sample sizes of the ethnic groups that comprised our ethnic minority group; Black, Asian, mixed and other, were too small with which to carry out a meaningful analysis.We acknowledge that due to the heterogeneity of the ethnic minority group, further differences in the risk factor profiles and outcomes of ACS may not have been fully gleaned. 30Population-based cohort studies from Scotland have demonstrated how the ethnicities within our ethnic minority group have different healthcare outcomes, with Pakistani patients identified as high risk of AMI and mortality, whereas Chinese patients typically have lower rates of AMI and better outcomes. 31,32We acknowledge that the ethnic minority group is markedly smaller than the white group, which means our study may not be sufficiently powered to detect statistically significant differences in outcomes between groups.

Conclusion
In our nationwide study of 118,177 patients with STEMI in the UK, we demonstrate that SMuRFless patients have a higher incidence of MACE, in-hospital mortality, and cardiac-mortality than those with ≥1 SMuRFs, which persists after adjusting for baseline demographics, hemodynamic status, Killip classification, cardiac arrest, and common comorbidities, but does not persist after adjusting for ICA or revascularisation.Ethnic minority patients were more likely to be younger, male and receive GDMT, undergo ICA and revascularisation regardless of SMuRF status.After adjusting for hemodynamic status, serum creatinine, Killip classification and cardiac arrest, there was no significant difference in our primary or secondary outcomes between White and ethnic minority patients.Further studies should be undertaken to identify these high-risk SMuRFless patients that do not have, or have undiagnosed conventional cardiovascular risk factors, and efforts made to improve awareness of the importance of GDMT for these patients.

Figure 1 .
Figure 1.Strengthening the Reporting of Observational studies in Epidemiology (STROBE) diagram detailing exclusion criteria.

Figure 2 .
Figure 2. Outcome comparison between patients and patients with SMuRFs.Figure legend: Primary Outcome comparison between SMuRFless patients and patients with SMuRFs.

Figure 4 .
Figure 4. Outcome comparison between ethnic minority and white SMuRFless patients.Figure legend: Primary Outcome comparison between ethnic minority and white SMuRFless patients MACE is defined as composite endpoint of in-hospital death and reinfarction.

Table 1 .
Demographic comparison between patients with ≥1 SMuRF and patients without SMuRFs stratified by ethnicity.